FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

• Published in: Nature communications Vol. 3; no. 1; p. 1000
• Main Authors: Chung, Young Min, Park, See-Hyoung, Tsai, Wen-Bin, Wang, Shih-Ya, Ikeda, Masa-Aki, Berek, Jonathan S., Chen, David J., Hu, Mickey C.-T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2012; Nature Publishing Group
• Subjects: 631/337/1427/2122; 631/67; 631/80/82/23; 631/80/86; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Checkpoint Kinase 2; Chromatin - genetics; Chromatin - metabolism; DNA Damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Humanities and Social Sciences; Humans; multidisciplinary; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Science; Science (multidisciplinary); Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2008

DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATM–Chk2–p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATM–Chk2–p53-mediated apoptotic programme following DNA damage. The protein ataxia-telangiectasia mutated (ATM) detects DNA damage and can trigger cellular apoptosis, but how this process is regulated at the molecular level is unclear. Here, Chung et al . show that the transcription factor FOXO3 controls the formation of ATM-containing signalling complexes at sites of DNA damage that trigger apoptosis.